A history of early-life stress (ELS) is an important risk factor for adult psychopathology, including major depression, anxiety disorders, and substance abuse. Preclinical studies of rodents and non-human primates demonstrate that early care-giving experiences play a critical role in the development of brain circuits involved in the regulation of stress-reactivity, affect and behavior. Changes in stress sensitivity and functioning of the HPA axis may underlie the association between stress and risk for psychiatric disorders. Converging lines of evidence from preclinical and clinical studies indicate that exposure to excessive glucocorticoid concentrations impairs neuroprotection and neurogenesis in the hippocampus and enhances dendritic branching in the amygdala, effects linked to the pathogenesis of depression and anxiety. Recent studies have identified several risk genes which appear to moderate the effects of stressors such as childhood maltreatment on risk for psychopathology. The precise mechanism of such interactions in humans is not known, but an elegant body of preclinical work on epigenetics shows complex interactions between genes and stressful experiences, with environmental perturbations causing changes in gene expression which leads to increased glucocorticoid secretion as well as behavioral sequelae of stress. In particular, low levels of maternal care in rodents have been linked to increased methylation of the glucocorticoid receptor gene in addition to exaggerated hormonal and behavioral responses to stress. Recent studies have begun to examine whether early-life stress leads to epigenetic modifications of the glucocorticoid receptor gene in humans. The goal of the present proposal is to determine whether adults with a history of childhood maltreatment have epigenetic modifications of the glucocorticoid receptor gene in comparison to adults without a history of maltreatment. Further, we aim to study the relationship between methylation of this gene and neuroendocrine responses to psychosocial and neurobiological challenge tests. The results of this study may yield information about the mechanism of the association between childhood maltreatment and risk for psychiatric disorders as well as the effect of early-life stress on alterations in stress reactivity and HPA axis function. Therapeutic interventions that target epigenetic modifications or otherwise mitigate stress responsivity in at-risk individuals may eventually have a role in the treatment and prevention of psychopathology related to maltreatment. PUBLIC HEALTH RELEVANCE: The proposed study seeks to examine epigenetic modifications of the glucocorticoid receptor gene in a sample of adults with and without a history of childhood maltreatment. In addition, the study aims to determine whether such changes are associated with altered cortisol and ACTH responses to psychosocial and neurobiological stress challenge tests. Results of this study may provide insight into the neurobiological markers and mechanisms of illness in individuals at-risk for depressive and anxiety disorders by virtue of childhood maltreatment. This information may contribute to future treatment and prevention efforts for stress- related disorders.